What is CAVIA?

One of the most prevalent cerebrovascular diseases in the elderly is cerebral amyloid angiopathy (CAA), characterized by vascular deposition of amyloid β protein (Aβ). CAA is increasingly recognized as an important cause of cognitive decline or dementia in old age. It has a high prevalence (10-50% of the general population), which increases with age.

Formation of CAA is most likely caused by failure of the normal clearance of Aβ from the brain. The normal transport of Aβ out of the brain parenchyma, across the blood-brain barrier, towards the circulation seems to be progressively deficient during aging due to, e.g. reduced interaction with cellular receptors, or enhanced aggregation of Aβ, eventually leading to CAA. Once clinical symptoms become evident, CAA is widespread in the brain, but at that time intervention is likely too late. Therefore, biomarkers of early CAA development are clearly needed for early diagnosis which will – in turn – allow for early intervention.

Early detection of CAA is a prerequisite for effective novel interventions, but the development of specific biomarkers for CAA is unfortunately lagging behind. Therefore, currently, the definitive diagnosis of CAA can only be made postmortem. Sensitive and specific diagnostic tests that allow detecting CAA during life are dearly needed. Such tests will (1) allow to establish a diagnosis of CAA at a higher level of confidence than is currently possible; (2) increase our understanding of the pathophysiology and natural history of the disease, which would significantly increase the chances of identifying targets for effective treatment; (3) help to assess the efficacy of candidate treatments in trials; (4) once effective treatments are available, early-stage diagnostic tests would aid in widening the therapeutic window of the treatment; and (5) finally, these tests would help to increase the safety of anticoagulation therapy in the elderly which are contra-indicated in CAA.

Several neuroimaging-based tests have been advocated for detection of CAA in vivo. The presence of lobar (micro) hemorrhages (a.k.a. microbleeds) on CT and MRI and limited subarachnoid blood collections or superficial siderosis can be suggestive – but not final – and probably late proof for the disease. Recent work by members of our project team strongly suggests that more specific diagnostic tests are within reach: (a) in cerebrospinal fluid (CSF) of CAA patients, an abnormal Aβ40/Aβ42 ratio is observed, distinguishing “pure” CAA from AD and supporting the concept of defining a potential CAA-specific Aβ profile; (b) several Aβ peptides and non-Aβ proteins have been demonstrated (by in vitro/ex vivo studies) to be associated with CAA formation, but not with senile plaques, and may serve as candidate biomarkers for CAA; (c) MRI measures of hemodynamic response to neuronal activation are delayed and suppressed in CAA, supporting the concept that CAA can be diagnosed via MRI sequences detecting functional consequences of CAA. Both these CSF and MRI techniques have the intrinsic power to detect early changes in CAA development.

In summary, the aim of this project is to develop and validate body fluid and neuroimaging methodologies to provide diagnostic tools to clinicians that will allow to detect CAA during life, to establish the contribution of CAA to cognitive decline and dementia, and to facilitate potential future personalized therapy.

Amyloid β protein

The amyloid β protein (Aβ) is the principal component of cerebral amyloid angiopathy (CAA). This is a small peptide of (maximal) 43 amino acids which aggregates in the blood vessel walls of the brain. There are multiple variants of Aβ, which may vary in length. For example, the variants with either 40 or 42 amino acids, Aβ40 or Aβ42, accumulate in CAA. In this project we will, amongst others, study if other Aβ variants are specifically associated with CAA formation, and how this accumulation affects the function of the cerebral blood vessels.